Adiponectin, a hormone produced primarily by adipose tissue, has emerged as a therapeutic target for two major diseases of the Western World, diabetes and cardiovascular disease. Adiponectin has antidiabetic, antiinflammatory and antiatherogenic properties, but circulates in low levels in obesity, insulin resistance, type 2 diabetes and cardiovascular disease. Although increasing data demonstrate pleiotropic effects of adiponectin in vascular cells, the role of adiponectin and adiponectin receptor expression in monocyte/macrophage inflammatory and atherogenic properties remain unclear. We have generated exciting new data demonstrating that 1) monocytes of insulin resistant vs. insulin sensitive subjects have more proinflammatory gene expression, 2) both adiponectin receptors are expressed on the monocyte and are increased in insulin resistance, 3) adiponectin activates monocyte 5' adenosine mono phosphate-activated kinase (AMPK) suppressing inflammatory genes activated by tumor necrosis factor-1, and 4) administration of adenoviral adiponectin inhibits accelerated atherosclerosis and promotes regression of existing atherosclerosis in mouse models. The major hypothesis of this project is that alterations in plasma adiponectin are associated with key changes in monocyte/macrophage genes that mediate inflammation, foam cell formation and that ultimately influence vascular inflammation, atherosclerosis progression and regression. The specific aims of this project are to: 1) define specific inflammatory and metabolic factors that regulate the adiponectin receptors, AdipoR1 and AdipoR2 in monocyte/macrophages, 2) define adiponectin gene targets that regulate monocyte/macrophage function, inflammatory gene expression, and foam cell formation in human and mouse monocyte/macrophages and determine the role of the AMPK and peroxisome proliferator activated receptor(PPAR)-1 signaling pathways in these processes, and 3) determine adenoviral adiponectin and adiponectin-dependent PPAR3 ligand effects in models of accelerated atherosclerosis progression (angiotensin II-infused LDLR-/- and old-LDLR-/-) and regression (old-LDLR-/-), and the role of macrophage adiponectin receptors in vascular inflammation and atherosclerosis using bone marrow transplantation with AdipoR1/R2 knockout mice. This project will be important to define specific protective actions of adiponectin and its receptors in the monocyte/macrophage; to identify potentially new candidate gene targets of adiponectin in monocyte/macrophages; and to define the role of these genes in attenuating the progression or promoting the regression of atherosclerosis in mouse cardiovascular disease models. The studies proposed herein will provide important new insights into our understanding of adiponectin, its potential importance as a therapeutic target in the metabolic syndrome, and its consequences for diabetes and coronary artery disease.